Patients with Alzheimer disease (AD) most commonly present with insidiously progressive memory loss, to which other spheres of cognitive impairment are added over several years. This loss may be associated with slowly progressive behavioral changes. After memory loss occurs, patients may also experience language disorders (eg, anomia) and impairment in their visuospatial skills and executive functions.
Patients with mild AD usually have somewhat less obvious executive, language, and/or visuospatial dysfunction. In atypical presentations, dysfunction in cognitive domains other than memory may be most apparent. In later stages, many patients develop extrapyramidal dysfunction.
Substantially less common, but biopsy or autopsy-proven, presentations include right parietal lobe syndrome, progressive aphasia, spastic paraparesis, and impaired visuospatial skills, which is subsumed under the visual variant of AD.
It is important to obtain a complete history not only from the patient but also from someone who knows the patient well. In addition, a family history of AD or other forms of dementia should be noted.
At the time of initial diagnosis, a complete physical examination, including a detailed neurologic examination and a mental status examination, should be performed to evaluate disease stage and rule out comorbid conditions. Initial mental status testing should include evaluation of the following:
Attention and concentration
Recent and remote memory
Praxis (ie, ability to perform skilled motor tasks without nonverbal prompting)
Cognitive features of early AD include memory loss, mild anomic aphasia, and visuospatial dysfunction. At all subsequent follow-up visits, a full mental status examination should be performed to evaluate disease progression and identify the development of any new neuropsychiatric symptoms.
Brief standardized examinations, such as the Mini-Mental Status Examination (MMSE), are less sensitive and specific than longer batteries that are specifically tailored to individual patients. Other examples include the Montreal Cognitive Assessment (MoCA) and the Saint Louis University Mental Status (SLUMS) examination. Nonetheless, screening exams have a role, particularly as a baseline. For more information, see the Medscape Reference article Screening for Cognitive Impairment.
A complete neurologic examination is performed to look for signs of other diseases that could cause dementia, such as Parkinson disease or multiple strokes.In patients with AD, the neurologic exam is generally normal but may reveal minor abnormalities such as hyposmia or anosmia.
Stages of Alzheimer Disease
AD can be classified into the following stages:
Preclinical Alzheimer disease
The pathologic changes associated with AD begin in the entorhinal cortex, which is near the hippocampus and directly connected to it. AD then proceeds to the hippocampus, which is the structure that is essential to the formation of short-term and long-term memories (see the images below). Affected regions begin to atrophy. These brain changes probably start 10-20 years before any visible signs or symptoms appear.
Memory loss, the first visible sign, is the main feature of amnestic mild cognitive impairment (MCI). Many scientists think MCI is often an initial, transitional clinical phase between normal brain aging and AD. For more information, see the Medscape Reference article Mild Cognitive Impairment.
Preclinical Alzheimer disease. Image courtesy of NPreclinical Alzheimer disease. Image courtesy of NIH. Preclinical Alzheimer disease. Image courtesy of NPreclinical Alzheimer disease. Image courtesy of NIH.
A patient with preclinical AD may appear completely normal on physical examination and mental status testing. At this stage, there is normally no alteration in judgment or the ability to perform activities of daily living.
Mild Alzheimer disease
As AD begins to affect the cerebral cortex, memory loss continues and impairment of other cognitive abilities emerges. This stage is referred to as mild AD. The clinical diagnosis of AD is usually made during this stage. Signs of mild AD can include the following:
Confusion about the location of familiar places (getting lost begins to occur)
Taking longer to accomplish normal daily tasks
Trouble handling money and paying bills
Compromised judgment often leading to bad decisions
Loss of spontaneity and sense of initiative
Mood and personality changes; increased anxiety
The growing number of plaques and tangles first damage areas of the brain that control memory, language, and reasoning (see the images below). Later in the disease, physical abilities decline. This leads to a situation in mild AD in which a person seems to be healthy but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually because the early signs can be confused with changes that can happen normally with aging.
Mild Alzheimer disease. The disease begins to affeMild Alzheimer disease. The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Image courtesy of NIH. Mild-to-moderate Alzheimer disease. Image courtesyMild-to-moderate Alzheimer disease. Image courtesy of NIH.
Acknowledging these signs of AD and deciding to seek diagnostic testing can be a hurdle for patients and their families to cross. In many cases, the family has a more difficult time handling the diagnosis than the patient does, probably because of apathy from the AD. Following the initial diagnosis, patients should be carefully monitored for depressed mood. Although it is common for patients with early AD to be depressed about the diagnosis, they rarely become suicidal.
Moderate Alzheimer disease
By the time AD reaches the moderate stage, damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy, and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families.
The symptoms of this stage can include the following:
Increasing memory loss and confusion
Shortened attention span
Problems recognizing friends and family members
Difficulty with language; problems with reading, writing, working with numbers
Difficulty organizing thoughts and thinking logically
Inability to learn new things or to cope with new or unexpected situations
Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night
Repetitive statements or movement; occasional muscle twitches
Hallucinations, delusions, suspiciousness or paranoia, irritability
Loss of impulse control (shown through behavior such as undressing at inappropriate times or places or vulgar language)
Perceptual-motor problems (such as trouble getting out of a chair or setting the table)
Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. In AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors. For example, patients may angrily refuse to take a bath or get dressed because they do not understand what the caregiver has asked them to do. If they do understand, they may not remember how to do what was asked.
This anger is a mask for underlying confusion and anxiety. Consequently, the risk for violent and homicidal behavior is highest at this stage of disease progression. Patients should be carefully monitored for any behavior that may compromise the safety of those around them.
For a person who cannot remember the past or anticipate the future, the world around them can be strange and frightening. Staying close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. A person with AD may constantly follow his or her caregiver and fret when the person is out of sight.
Judgment and impulse control continue to decline at this stage. For example, taking off clothes may seem reasonable to a person with AD who feels hot and does not understand or remember that undressing in public is not acceptable.
Severe Alzheimer disease
In the last stage, severe AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further (see the images below). Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish.
Severe Alzheimer disease. In the last stage of AD,Severe Alzheimer disease. In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Image courtesy of NIH. Severe Alzheimer disease. Image courtesy of NIH. Severe Alzheimer disease. Image courtesy of NIH.
Other symptoms can include the following:
Seizures, skin infections, difficulty swallowing
Groaning, moaning, or grunting
Lack of bladder and bowel control
In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.
Clinical Guidelines for Diagnosis
Clinical guidelines for the diagnosis of AD have been formulated by the National Institutes of Health-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA); the American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision, Text Revision (DSM-IV-TR); and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) workgroup released new research and clinical diagnostic criteria for AD.
The NIH-ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or delirium. Toxic metabolic conditions and brain neoplasms must also be excluded as potential causes of the patient’s dementia.
The focus of the 2011 NIA-AA criteria is the need to create a more accurate diagnosis of preclinical disease so that treatment can begin before neurons are significantly damaged, while they are more likely to respond. Therefore, the report includes criteria for diagnosis of the following:
Asymptomatic, preclinical AD (for purposes of research, not clinical diagnosis) Mild cognitive impairment (MCI), an early symptomatic but predementia phase of AD AD dementia
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision(DSM-IV-TR) lists 6 diagnostic criteria, labeled A-F, for dementia of the Alzheimer type (see Table 1, below). These guidelines are widely believed to be 90-95% accurate (as histopathologically verified) when followed carefully. They are important not only for routine management but also for selecting and enrolling patients in therapeutic trials.